Tapentadol shows lower intrinsic efficacy at µ receptor than morphine and oxycodone

Preeti Manandhar, Mark Connor*, Marina Santiago

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
239 Downloads (Pure)

Abstract

Tapentadol is a centrally acting analgesic with a dual mechanism of action. It acts as an agonist at the µ receptor and inhibitor of noradrenaline reuptake. Clinical trials suggest similar analgesic efficacy of tapentadol, oxycodone, and morphine in acute and chronic pain. Given the limited information about the molecular actions of tapentadol at the µ receptor, we investigated the intrinsic efficacy of tapentadol and compared it with other opioids. β-chlornaltrexamine (β-CNA, 100 nM, 20 min) was used to deplete spare receptors in AtT20 cells stably transfected with human µ receptor wild-type (WT). Opioid-mediated changes in membrane potential were measured in real-time using a membrane potential-sensitive fluorescent dye. Using Black and Leff's operational model, intrinsic efficacy relative to DAMGO was calculated for each opioid. Tapentadol (0.05 ± 0.01) activated the GIRK channel with lesser intrinsic efficacy than morphine (0.17 ± 0.02) and oxycodone (0.16 ± 0.02). We further assessed the signaling of tapentadol in the common µ receptor variants (N40D and A6V) which are associated with altered receptor signaling. We found no difference in the response of tapentadol between these receptor variants.
Original languageEnglish
Article numbere00921
Pages (from-to)1-12
Number of pages12
JournalPharmacology Research & Perspectives
Volume10
Issue number1
DOIs
Publication statusPublished - Feb 2022

Bibliographical note

Copyright the Author(s) 2022. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • µ receptor
  • G protein
  • intrinsic efficacy
  • operational model
  • opioids
  • pain
  • receptor depletion
  • signaling
  • single nucleotide polymorphism

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